Metabolic Syndrome in Liver Transplantation: The Elephant in the Room

Hepatitis C virus (HCV) is the leading indication for liver transplantation among adults in the United States.1 After transplantation, infection of the allograft by HCV is invariable, and the natural history of HCV is greatly accelerated in the posttransplant setting. HCV-induced allograft hepatitis and fibrosis/cirrhosis occur in 70% to 80% and 10% to 21% of recipients at 5 years, respectively.2, 3 Once histological cirrhosis develops, progression is rapid, with a high risk of clinical decompensation.4 Indeed, HCV infection significantly impairs patient and allograft survival after liver transplantation, with a 23% increased rate of death and a 30% increased rate of allograft failure.5 HCV treatment post-transplant is difficult; although sustained virologic response is possible, antiviral therapy certainly is not optimal, with side effects limiting its use.6 Studies, therefore, have been performed that look at factors associated with fibrosis progression and poor survival, including the year of transplantation,7 viral load,8 genotype,3 use of steroids or OKT3,9, 10 cytomegalovirus,11 and donor age.12 DM, diabetes mellitus; HCV, hepatitis C virus; IR, insulin resistance; MS, metabolic syndrome. In this issue of Liver Transplantation, Hanouneh et al.13 provide another piece of this puzzle. The authors performed a retrospective analysis of 95 liver recipients with recurrent HCV to determine if metabolic syndrome (MS) was associated with fibrosis progression. MS was defined according to the National Cholesterol Education Program Adult Treatment Panel III criteria14 at 1 year post-transplant, and the first biopsy demonstrating histological stage F1 or greater (with the Ludwig-Batts scoring system) was used for analysis. Overall, 50% of recipients had MS; of these, 80.5% had evidence of progression. On univariable analysis, the 4-month HCV viral load, cytomegalovirus infection, use of antiviral therapy, diabetes mellitus (DM), and presence of MS were associated with fibrosis progression. On multivariable analysis, only the 4-month HCV viral load and use of steroids were independent predictors. However, when the authors looked at the interaction (ie, effect modification) between MS and the follow-up time, they found that MS was independently associated with fibrosis progression when the follow-up time exceeded 1 year post-transplant with a hazard ratio of 6.3 (1.4–28.7, P = 0.017). These results are not entirely surprising. In the nontransplant population, hepatitis C infection has been linked to steatosis, DM, and insulin resistance (IR), and each has been associated with fibrosis progression.15-17 HCV infection may induce the development of IR via interference with the tyrosine phosphorylation of the insulin receptor substrate, which in turn affects multiple steps in the insulin signaling pathway.18, 19 Proposed mechanisms for fibrosis include the induction of proinflammatory and profibrotic mediators such as tumor necrosis factor and interleukin-6 and likely share similarities with those involved in nonalcoholic fatty liver disease.17 Leandro et al.20 recently performed a meta-analysis of 3068 HCV-positive patients from the United States and Europe and demonstrated that steatosis was associated with fibrosis, even after adjustments for inflammation, gender, body mass index (BMI), diabetes, and genotype (odds ratio = 1.66, P < 0.001). Furthermore, there is an association between HCV and type 2 DM21; in HCV-positive patients, DM is associated with a risk of progression to severe fibrosis both pre-transplant17 and post-transplant22 even in the absence of steatosis. In the 1 published study directly looking at IR post-transplant in patients with HCV, Delgado-Borrego et al.23 found that IR (as measured via homeostasis model assessment) was 77% higher in HCV-positive recipients versus HCV-negative recipients during the first year post-transplant even after they controlled for BMI. IR, in fact, has been shown to be a major determinant of advanced fibrosis in patients with HCV even after researchers controlled for steatosis.24 Moreover, IR has been associated with a poor response to therapy with interferon and ribavirin, independently of BMI and steatosis.25 MS is clearly associated with IR, and so it is not surprising that Hanouneh et al.13 observed that MS is associated with fibrosis progression after liver transplantation. However, are the results from this study valid? Several methodological limitations of this study need to be discussed. This study was not specifically powered to look at MS, and its sample size is small. The first biopsy that demonstrated stage F1 or greater was used for the time-to-progression analysis, but the authors defined their predictor variable, MS, at a time period (1 year) that occurred in many instances after the biopsy demonstrating progression; this made their analysis somewhat flawed. Also, the seemingly large interaction hazard ratio for the association of MS and fibrosis progression when the follow-up time exceeds 1 year needs to be looked at in the context of this study's short duration of follow-up as patients without fibrosis were followed for a median time of 12.8 (8.7–26.3) months and patients with fibrosis were followed for a median time to progression of only 9.5 (5.4–16) months. In fact, the overall follow-up time of the entire cohort was only 1.6 (0.99–2.5) years. Despite this study's limitations, the authors should be commended for extending what is known about risk factors for fibrosis progression in HCV to the transplant population, and I suspect that the association between MS and fibrosis will persist in subsequent studies with longer follow-up duration and larger sample sizes. So, what should we take away from Hanouneh et al's article13? It is most striking that 50% of patients had MS at 1 year post-transplant: 57.9% in the progression cohort and 32% in the nonprogression cohort. These numbers are consistent with the 1 study that has directly addressed the issue of MS post–liver transplantation: Laryea et al.26 reported MS prevalence post-transplant to be 58%. It has been well recognized that accelerated cardiovascular disease is a leading cause of death and allograft loss in long-term survivors of both heart and kidney transplants. Liver candidates have a low prevalence of cardiovascular risk factors pre-transplant and traditionally have been considered to be at low risk for cardiovascular complications post-transplant. However, there are many factors that may predispose liver recipients to cardiovascular disease and MS, including immunosuppression use, changes in lipoprotein metabolism induced by the new liver, changes in patients' habits, and the underlying liver disease itself (nonalcoholic fatty liver disease and HCV). Indeed, after liver transplantation, the incidence of hypertension is 40% to 85%,13, 27 the incidence of dyslipidemia is 20% to 66%,13, 27, 28 the incidence of DM is 5% to 60%,13, 27, 29 and the incidence of obesity is 20% to 40%.13, 27 Elevated blood pressure increases the risk for cardiovascular disease, and guidelines have been established for the general population, which include more stringent diagnosis and treatment criteria in the setting of coexistent DM or chronic renal insufficiency.30 Dyslipidemia also increases cardiovascular disease risk, and guidelines have been established for the general population.14 Recent guidelines for renal transplant recipients advise a much more aggressive approach to its recognition and management.31 Diabetes (and to a similar extent glucose intolerance and IR) amplifies other cardiovascular risk factors in the general population and is associated with a 2- to 4-fold excess risk of cardiovascular disease.32 Post-transplant, it is associated with increased morbidity and mortality.33 With the high prevalence of hypertension, dyslipidemia, DM, and obesity, it is not surprising that liver recipients develop MS. According to the Third National Health and Nutrition Examination Survey, 1999–2000, the prevalence of MS in the general population is 26.7%,34 and it is well established that MS is associated with cardiovascular disease and all-cause mortality.35 The exact magnitude of this problem in the liver transplant population is yet to be determined, but with the high prevalence of MS (and its individual components), as demonstrated in studies such as the one by Hanouneh et al.,13 we can expect to see similar morbidity and mortality. In fact, in the study by Laryea et al.,26 the presence of MS was associated with a statistically significant higher rate of vascular events (30% versus 8%, P = 0.003). Chronic renal insufficiency after liver transplantation is common and well recognized.36 The well-known association between calcineurin inhibitor therapy and posttransplantation renal dysfunction has led to the development of calcineurin-free immunosuppressive regimens. The transplant community has not, however, been as aggressive in managing other cardiovascular risk factors. There are no specific guidelines for the treatment of cardiovascular complications in liver recipients, it is unknown whether or not recipients are receiving adequate management, and what group of providers can best deliver optimal care of these conditions has been debated.37 In the setting of chronic medical diseases (in this case liver transplantation), Redelmeier et al.38 demonstrated that ancillary disorders are often undertreated. We do know that as patients are living longer after liver transplantation, cardiovascular complications are emerging as major causes of morbidity and mortality. Recent data indicate that accelerated cardiovascular disease is second only to malignancy as a cause of late mortality.39 As more transplant recipients survive into their first and second decades post-transplant, it is likely that more will develop metabolic complications and MS. How can we move forward with this knowledge? It is imperative to address the issue of MS in the context of liver transplantation as a whole and not just as it pertains to HCV patients. The transplant community must develop new strategies and guidelines to modify cardiovascular risk factors (perhaps more aggressive targets, as with kidney recipients) to improve long-term survival. Prospective multicenter studies are needed to determine the magnitude of the problem. Our goal as transplant physicians should include not only prevention of fibrosis progression but also cardiovascular risk factor modification. It is time to face the elephant in the room!